This invention relates generally to the field of antibodies that specifically bind to surface antigens of human cells, particularly human T lymphocytes or "T cells" ; it also relates to methods for using those antibodies.
The antigen-specific immune system comprises a variety of differentiated T cells (thymus-derived lymphocytes) and B cells (bone-marrow-derived lymphocytes). Different categories and sub-categories of lymphocytes are defined by expression of different cell-surface antigens. Specifically, various categories and sub-categories of T cells have been identified by characteristic patterns of cell-surface antigen expression. While some functional correlations with these antigens have emerged, many aspects of T-cell function remain to be elucidated.
McMichael and Gotch provide a review of T-cell antigens and antibodies supplied by a large number of workers in the field. They categorize the antibodies by so-called cluster designations ("CD's") of the IUIS-WHO nomenclature committee. See, McMichael and Gotch, "T-cell antigens: New and previously defined clusters" Ch. 5.1 in Leucocyte typing III, Springer-Verlag, Heidelberg (1987). See also, Bernard et al., Leucocyte typing, Springer-Verlag, Heidelberg (1984); and Reinhertz et al., Leucocyte typing II. Springer-Verlag, Heidelberg (1986). Among the widely accepted categories of T cells are: so-called CD4+(or T4) cells, which comprise the majority of the helper-inducer cells and are a specific target of the AIDS virus; and CD8+(or T8) cells, which comprise the majority of the cytotoxic and suppressor cells. T4 cells bear the CD3 antigen which is generally characteristic of all T cells and the CD4 antigen which is specific among T cells to T4 cells. T8 cells bear CD3 and CD8 antigens.
Various monoclonal antibodies which differentiate T-cell subpopulations are known (Ortho Pharmaceuticals, Raritan, N.J.) U.S. Pat. Nos. 4,361,549 (OKT3 ATCC CRL 8001); 4,361,550 (OKT8, CRRL 8014); 4,363,799 (OKT1); 4,364,932 (OKT5); 4,364,933 (OKT6); 4,364,934 (OKT9); 4,364,935 (OKT10); 4,364,936 (OKM1); 4,364,937 (OKT11); and 4,381,295 (OKT4, ATCC CRL 8002).
CD3, in combination with Ti, the antigen binding structure, forms the T cell receptor complex (TCR). The major function of TCR appears to be in signal transduction (reviewed by Allison and Lanier, Ann. Rev. Immunol. 5:503-540 (1987)). The effects on T cell function, when antibody binds to the CD3 antigen, are complex.
Van Wauwve et al., J. Immunol. 1124:2708-2713 (1980) reported that OKT3 monoclonal antibody (MAB), when provided in solution containing peripheral blood mononuclear cells, induces mitogenesis of the T lymphocytes. Monoclonal antibodies are generally bivalent, i.e., they have two FAB sites that specifically recognize the same target. Thus, it has been proposed that T cell proliferation is initiated by cross-linking of two CD3 antigens by the bivalent anti-CD3 monoclonal antibody (OKT3). See, e.g., Allison and Lanier, Ann. Rev. Immunol. 5:503-540 (1987). Van Wauwe and others who have presented monovalent anti-TCR antibody report weak or ineffective proliferation. (Kaye et al. J. Exp. Med. 159:1397-1412 (1984)).
Others have studied the effect of anti-CD4 or anti-CD8 antibody on anti-CD3-induced-T-cell proliferation. In one case, the effect was reported to be inhibitory, and in another case it was reported to augment proliferation. Bank and Chest, J. Exp. Med. 162:1294 reported that binding of the CD4 by MAB in a soluble state sends a strong inhibitory signal. Fleischer et al., J. Immunol. 136:1625 showed that soluble CD8 binding also sends an inhibitory signal. In contrast, Anderson et al., J. Immunol. 139:678-682 disclosed that when the anti-CD4 or anti-CD8 MAB is absorbed to the same bead surface as an anti-CD3 MAB, there is a strong augmentation to proliferation. Emmrich et al., Proc. Nat'l. Acad. Sci. USA 83:829808301 (1986) also reported that anti-CD8 MAB and anti-CD3 MAB, when attached to the same plastic surface, significantly enhanced proliferation of CD8 cells.
Still others have studied the effect of linking antibodies which are exclusively expressed on different cell types. For example, Perez et al., J. Exp. Med. 163:166-178 (1986) report that T cells, sensitized with anti-CD3-antibody which has been covalently linked to antibodies to tumor cell targets, will lyse the tumor targets. Stearz and Bevan, Proc. Nat'l. Acad. USA 83:1453-1457 (1986) disclose a mouse hybrid hybridoma cell line produced from parental hybridomas whose antibodies recognize, respectively, murine T-cell receptor complex (F23.1, a murine IgG2a) and a murine Thy-1.1 alloantigenic determinant. The bispecific monoclonal antibodies produced by the hybrid hybridoma induced lysis of cells bearing the Thy-1.1 target antigen.
The binding regions of bispecific monclonal antibodies have been further modified in an attempt to increase binding to target cells and thereby further stimulate the release of cytokines. Immunol. Today 12:51 (1991).
Moretta et al., J. Exp. Med. 159:921 (1984) reported the relative effectiveness of anti-CD3, anti-CD4, and anti-CD8 MABs in blocking cytolytic functions and found considerable clonal heterogeneity. These experiments were done in the continuous presence of the MABs.